Bicarbonate is a vital component of secretions from exocrine glands such as salivary glands, pancreas, duodenum, reproductive organs, sweat glands and the airways. It plays a critical role in numerous physiological functions such as maintaining oral and reproductive health, digestion, and airway defense (13, 90, 96, 107, 143). Loss of HCO3- transport is responsible for many pathological changes in Cystic Fibrosis (CF) including: abnormal mucous secretion in the intestine and airways (63, 65, 107), destruction of pancreas (53, 54);meconium ileus and distal intestinal obstructive syndrome (41, 104). CFTR mutations not only affect Cl-, but also HCO3- transport (24, 26, 27, 77, 102, 125, 150). Hence, therapeutic strategies aimed at curing CF must consider how different CF mutations affect CFTR-HCO3- channel function. Early studies mostly focused on the effects of CF mutations on either CFTR Cl- channel function (44, 79-81, 171) or on CFTR dependent HCO3- exchange function (23, 24, 72, 97) mostly in heterologous models provided valuable insights in to the role of CFTR in health and disease. Furthermore promising new therapeutic drugs have been reported to have at least partially restored the Cl- channel function of mutant CFTR mostly in ex vivo models (7, 37, 50). These and other potentially valuable drugs deserve immediate attention by way of testing their efficacy on a readily accessible native human tissue with minimal risk to human subjects. Human sweat ducts whose apical membrane richly and exclusively express CFTR are more accessible than any other CF affected internal human organ. Besides, in the absence of a Cl-/ HCO3- exchange function and alternative Cl- channels (125) in the apical membrane, CFTR is the only anion conductive pathway. Thus, this model offers an exceptional opportunity to investigate the properties of regulation and the effects of different disease causing mutations on the Cl- and HCO3- channel functions of CFTR in a native human tissue in relative isolation. Preliminary evidence indicated that the Cl- and HCO3- conductances of CFTR are not only regulated differently in normal epithelial cells, but are also unevenly affected by different CF mutations thereby determining the severity of the disease (124). Hence, the aims of this study are to determine the properties of regulation of CFTR mediated HCO3- conductive function and evaluate the therapeutic potential of new CF drugs using normal and CF affected native human epithelial tissue. We will accomplish these aims by testing the central hypothesis that "the regulation and the magnitude of CFTR HCO3- conductance are abnormal and mutation specific in cystic fibrosis". Successful execution of the project should a.) enhance our knowledge of the role of CFTR-HCO3- conductance in CF pathology, b.) aid in identifying those mutations that require therapies aimed at compensating derailed HCO3- transport and c.) help identify potential therapeutic drugs that can actually correct abnormal electrolyte transport defects in CF in the native physiological background. PUBLIC HEALTH RELEVANCE: Bicarbonate is a vital component of secretions from salivary glands, the pancreas, the duodenum, reproductive organs, sweat glands and the airways. CFTR bicarbonate transport plays critical role in maintaining oral and reproductive health, digestion, and airway defense. The objectives of this study are to determine the properties of regulation of CFTR mediated bicarbonate conductance and evaluate therapeutic potential of Cystic Fibrosis drugs using normal and CF affected native human sweat duct as model system.